This proposal is submitted as an exploratory research center grant in response to the PA (PAR-03-046) "DEVELOPMENTAL CENTERS FOR RESEARCH ON COMPLEMENTARY AND ALTERNATIVE MEDICINE (DCRC)" It focuses on PA objectives by the development of basic, translational, and clinical research to establish the feasibility and scientific rationale for use of mushroom extracts as immunopotentiating agents. Because of their ability to enhance the immune system, mushrooms have been used for centuries to treat a number of diseases including infections, autoimmune diseases, and cancer. Mushrooms extracts contain a number of bioactive substances that can induce the immune system, specifically, beta-glucans, triterpenes, and ergosterols. PSP and PSK, concentrated forms of Trametes Versicolor (Tv) containing high levels of polysaccharide beta glucans (13-glucan), have been popularized in Asia as effective anti-neoplastic agents. A number of investigators have shown that these Tv derivatives can individually induce NK-cell activity and tumor regression. However, the efficacy of the complex Tv extract as an immunopotentiating agent and whether it has equal or superior activity to the commercially available derivatives has yet to be determined. There exists a potential for synergism and superior activity of the complex Tv extract compared to the commercially available derivatives. We hypothesize that 13-glucans in Tv represent a major constituent that gives the ability of these extracts to upregulate the immune system causing tumor regression and amelioration of treatment side effects. The rationale that underlies this investigation is that once we understand that 13-glucans in complex Tv extracts can induce an immune response, we can devise approaches to study regulation of the immune system, and strengthen the scientific rationale of 13-glucan/mushroom extract action as therapeutic strategy for cancer. To test this hypothesis, we have assembled a group of projects that will address the following specific aims. In Project 1, we will investigate if Tv extracts are superior to purified b-glucan derivatives in stimulating an immune response in human-derived peripheral blood lymphocytes and whether oral intake of Tv in normal volunteers will stimulate the immune system. In Project 2, we will 1) determine optimal dose and schedule of Tv extracts to invoke an immune response in a tumor-bearing murine model, 2) assess the effect of nonglucan constituents on the biodistribution and activity of fluorescently-labeled 13-glucan purified from our Tv extracts; 3) determine the necessity of an intact immune response for Tv 13-glucans to induce tumor regression and ameliorate treatment side effects. In Project 3, we will perform a Phase 1/11trial to determine the ability of complex Tv extracts to provoke an immune response in breast cancer patients undergoing lumpectomy and radiation. These projects will be support by three cores: Administrative, Clinical, and Bioanalytical, which will interact with each of the projects. This DCRC will represent the first step in a programmatic effort to study and understand the role of mushrooms in the treatment of immune-responsive disease. We expect that this data will lead to the creation of phase II clinical trials and application for further NIH funding in the future.